Background: Physical activity (PA) has been positively associated with health-related quality of life (HRQoL) among cancer patients and family caregivers. However, there has been no relevant research for patient-caregiver dyads. Methods: Path analysis, based on the actor–partner interdependence model (APIM), was used to examine the relationship between physical activity and health-related quality of life and explore the mediating role of emotional distress in 233 dyads.